Substituted 1-sulfonylbenzimidazoles

ABSTRACT

Certain 1-sulfonyl-2,5(6)-substituted-benzimidazole compounds are useful as antiviral agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of our copending application Ser. No. 760,803, filedJan. 19, 1977, and issued Oct. 3, 1978 as U.S. Pat. No. 4,1118,573.Application Ser. No. 760,803 was, in turn, a division of our thencopending application Ser. No. 634,942, filed Nov. 24, 1975, and issuedApr. 19, 1977, as U.S. Pat. No. 4,018,790. Application Ser. No. 634,942was, in turn, a continuation-in-part of our then copending applicationSer. No. 574,202, filed May 8, 1975, and abandoned after the filing ofapplication Ser. No. 634,942. Application Ser. No. 574,202 was, in turn,a continuation-in-part of our then copending application Ser. No.484,841, filed July 1, 1974, and abandoned after the filing ofapplication Ser. No. 574,202.

BACKGROUND OF THE INVENTION

The incidence of viral upper respiratory disease is immense. It has beenestimated that nearly a billion cases annually appear in the UnitedStates alone. Studies performed in England (Tyrell and Bynoe, 1966)indicated that 74 percent of persons having colds were infected withrhinoviruses. Because more than 80 strains of rhinoviruses are alreadyidentified, the development of a practical rhinovirus vaccine is notfeasible, and chemotherapy appears to be the more desirable approach.

The ability of chemical compounds to suppress the growth of viruses invitro is readily demonstrated by using a virus plaque suppression testsimilar to that described by Siminoff, Applied Microbiology, 9(1),66(1961).

It is the purpose of this invention to provide novelsulfonylbenzimidazole compounds which inhibit the growth of certainviruses, including 25 strains of rhinoviruses, polio (types I, II, III),Coxsackie (A9, A21, B5), echo virus (strains 1, 2, 3, 4) and Mengovirus. Rhinoviruses are known to be associated with the common cold. Thecompounds of the invention are potentially useful in the treatment ofsuch virus infections in warm-blooded animals and humans.

Certain antifungal 1-dimethylaminosulfonyl-2-aminobenzimidazolecompounds have been disclosed in German published application No.2,206,010, published Aug. 16, 1973, and in U.S. Pat. No. 3,853,908.

SUMMARY OF THE INVENTION

This invention provides pharmacologically useful sulfonyl benzimidazolecompounds represented by Formula I ##STR1## wherein

R₁ is C₁ -C₅ alkyl, C₃ -C₇ cycloalkyl, phenyl, furyl, thienyl,thiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, 2-methylamino-1,3,4-thiadiazol-5-yl orR₄ R₅ NH--, wherein R₄ and R₅ are independently C₁ -C₃ alkyl and whentaken together with the nitrogen atom to which they are attached, arepyrrolidino, piperidino or morpholino;

R₂ is hydrogen, formyl, acetyl or propionyl;

R₃ is C₁ -C₈ alkoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, (C₃-C₇ cycloalkyl)oxycarbonyl, (C₃ -C₇ cycloalkyl)methyloxycarbonyl, 1-(C₃-C₇ cycloalkyl)ethyloxycarbonyl, benzyloxycarbonyl,α-methylbenzyloxycarbonyl, phenoxycarbonyl, C₁ -C₈ alkoxycarbonylmethyl,1-(C₁ -C₈ alkoxycarbonyl)ethyl, hydrazinocarbonyl, carboxy, carboxamido,N-(C₁ -C₄ alkyl)carboxamido, N-(C₁ -C₄ alkoxy)carboxamido,hydroxymethyl, cyano, methylsulfonyl or trifluoromethyl; and R₃ is atthe 5 or 6 position.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The present invention relates to new organic sulfonyl compounds that areuseful as antiviral agents and to methods for their production. Thecompounds of the invention are prepared by reacting a tautomericbenzimidazole compound of the Formula II ##STR2## with a sulfonylchloride compound having the formula R₁ SO₂ Cl wherein R₁, and R₃ are asdefined hereinabove to yield a compound according to Formula I whereinR₂ is hydrogen.

The term "tautomeric benzimidazole" refers to a benzimidazole reagentwhich can be substituted at either nitrogen atom with a hydrogen atom.The benzimidazole reactant, unsubstituted on nitrogen and bearing an R₃substituent group at the 5 position of the benzene moiety, has acorresponding tautomeric form with which it is in equilibrium whereinthe substituent resides alternatively at the 6 position. The isomermixture can be indicated by numbering the alternate positions as 5(6).As a consequence of such tautomerism, the reaction of a 5(6) substitutedbenzimidazole with a sulfonyl chloride produces isomeric mixtures of5(6)-substituted sulfonylbenzimidazoles.

The following definitions refer to the various terms used throughoutthis disclosure. The term "furan" refers to the furan radical attachedat the 2 or 3 position. The term "thienyl" refers to the thiopheneradical attached at the 2 or 3 position. The term "thiazol-2-yl" or"2-thiazole" refers to the thiazole radical attached at the 2 position.The term "1,3,4-thiadiazole-2-yl" or "thiadiazol-2-yl" refers to the1,3,4-thiadiazole radical attached at the 2 position. The term"2-methyl-1,3,4-thiadiazol-5-yl" or"2-methylamino-1,3,4-thiadiazol-5-yl" refers to a2-substituted-1,3,4-thiadiazole radical attached at the 5 position.

The term "C₁ -C₈ alkyl" refers to the straight and branched aliphaticradicals of one to eight carbon atoms including methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl,sec-amyl, sec-isoamyl (1,2-dimethylpropyl), tert-amyl(1,1-dimethylpropyl), neopentyl, hexyl, isohexyl (4-methylpentyl),sec-hexyl (1-methylpentyl), 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl,1,1,2-trimethylpropyl, heptyl, isoheptyl (5-methylhexyl), sec-heptyl(1-methylhexyl), 1-ethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylphenyl,1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl,1,1,3-trimethylbutyl, octyl, isooctyl (6-methylheptyl),sec-octyl(1-methylheptyl), tert-octyl(1,1,3,3-tetramethylbutyl and thelike. The term C₁ -C₈ alkyl includes within its definition the terms "C₁-C₃ alkyl", "C₁ -C₄ alkyl", "C₁ -C₅ alkyl", and "C₁ -C₇ alkyl". The term"C₁ -C₈ alkyl carbinol" refers to the straight and branched aliphaticalcohols in which alkyl group of one to eight carbon atoms asexemplified in the term "C₁ -C₈ alkyl" above are substituted with an OHgroup. The term "C₁ -C₈ alkoxy" includes ether radicals of one to eightcarbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, amyloxy, isoamyloxy, 1,2-dimethylpropoxy,tert-amyloxy, neopentyloxy, hexyloxy, (2-methyl-1-pentyl)oxy,(4-methyl-2-pentyl)oxy, (2-ethyl-1-butyl)oxy, heptyloxy, 2-heptyloxy,octyloxy, 2-octyloxy, (2-ethylhexyl)oxy, isooctyloxy,(2,2,4-trimethyl-1-pentyl)oxy, and the like. The term "C₁ -C₈ alkoxy"includes within its definition the term "C₁ -C₄ alkoxy".

The term "C₃ -C₇ cycloalkyl" refers to the saturated alicyclic rings ofthree to seven carbon atoms such as cyclopropyl, methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-, 2-, 3- or 4-methylcyclohexyland cycloheptyl. The term "C₃ -C₇ cycloalkylmethyl" refers to a methylradical substituted with saturated alicyclic rings of three to sevencarbon atoms as exemplified in the term "C₃ -C₇ cycloalkyl", such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl and the like. The term "C₃ -C₇cycloalkyl alcohol" refers to cyclopropanol, cyclobutanol,cyclopentanol, cyclohexanol and cycloheptanol. The term "C₃ -C₇cycloalkylmethanols" refers to methanol substituted on the carbon withsaturated alicyclic rings of three to seven carbon atoms; for examplecyclopropylmethanol, cyclobutylmethanol, cyclopentylmethanol,cyclohexylmethanol, and cycloheptylmethanol. These C₃ -C₇ alicyclicmethanols are available from the corresponding C₃ -C₇ alicycliccarboxyaldehydes by reduction. The term "1-(C₃ -C₇ cycloalkyl)ethanol"refers to ethanols which are substituted on the carbon atom in the 1position with saturated alicyclic rings of three to seven carbon atoms;for example, 1-cyclopropylethanol, 1-cyclopentylethanol,1-cycloheptylethanol and the like. These ethanols are available from thecorresponding 1-(C₃ -C₇ cycloalkyl)methyl ketones by reduction. The term"1-(C₃ -C₇ cycloalkyl)ethyl" refers to ethyl radicals substituted on thecarbon atom in the 1 position with saturated alicyclic rings of three toseven carbon atoms. The term "C₁ -C₄ alkylamine" refers to aliphaticamines of one to four carbon atoms such as methylamine, ethylamine,propylamine, isopropylamine, butylamine, sec-butylamine and the like.The term "C₁ -C₄ alkoxyamine" refers to methoxyamine, ethoxyamine,propoxyamine, isopropoxyamine, butoxyamine and the like.

In the above reaction the preferred reactants are benzimidazolecompounds (II) bearing R₃ substituents which are chemically inert to thesulfonyl chloride reactant. The benzimidazole compound and the sulfonylchloride are normally employed in approximately equimolar quantities,although an excess of either can be used if desired without adverseeffects on the yield of product. The reaction can be carried out in anynumber of unreactive solvents, including acetone, dimethoxyethane(glyme,DME), tetrahydrofuran (THF), tertiary amides such asN,N-dimethylformamide (DMF), and chlorinated hydrocarbons suchdichloromethane, dichloroethane and chloroform. The reaction medium mayalso contain added base to serve as an acid-binding agent. Some examplesof suitable bases for this purpose are pyridine, triethylamine,N-methylmorpholine, sodium bicarbonate, and sodium hydride. A preferredsolvent medium for the reaction is acetone containing triethylamine ortetrahydrofuran with DMF containing sodium hydride as a base.

The reaction is best carried out at a temperature between roomtemperature and the reflux temperature of the solvent system employed.Preferably, the reaction is carried out at reflux temperature, and atthis temperature, the reaction is substantially complete within 1 to 48hours.

The product of the reaction is a 1-sulfonylbenzimidazole compound,hereinafter called the sulfonylbenzimidazole compound. The product maybe isolated by filtering the reaction mixture and concentrating thefiltrate to induce crystallization. Alternatively, the reaction mixturecan be evaporated to dryness and the residue treated with a suitablesolvent such as acetone or methanol to separate and remove any insolublematerial. The solution containing the sulfonylbenzimidazole compound isconcentrated to crystallize the product or it is evaporated to give asecond residue, which is dissolved in methanol for example. Thesulfonylbenzimidazole compound is recovered from the methanol bycrystallization.

The reaction of the tautomeric benzimidazole compound and the sulfonylchloride generally provides a 1:1 mixture of 5- and 6-substitutedsulfonylbenzimidazole isomers. The isomers are separable by fractionalcrystallization or by column chromatography. Usually the 6-isomercrystallizes first from a solution of the mixture. For example, whenethyl 2-amino-5-benzimidazolecarboxylate is reacted withdimethylsulfamoyl chloride in acetone containing triethylamine, ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate crystallizesfirst from the reaction mixture. The acetone mother liquors containpredominantly ethyl1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate and residualamounts of the 6-isomer. The isomers can be identified by their nuclearmagnetic resonance spectra in the phenyl proton region (7.0 to 8.3 ppm).

Some of the compounds of the invention can be prepared by performingchemical operations such as acetylation, hydrolysis or reduction on thecorresponding sulfonylbenzimidazole precursor. When the reactions areperformed on a precursor which is an isomeric mixture ofsulfonylbenzimidazoles, the isomeric products can be separated bymethods such as fractional crystallization or chromatography.

The 2-formamido, 2-acetamido or 2-propionamido sulfonylbenzimidazolescan be prepared preferably by acylating the corresponding 2-aminosulfonylbenzimidazole (Formula I, R₂ is hydrogen) with the anhydride ofacetic or propionic acid or the mixed anhydride of formic and aceticacids. For example, a mixture of ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate isomers isstirred with acetic anhydride at room temperature to provide ethyl1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate as amixture. The isomeric 2-acetamido sulfonylbenzimidazoles can beseparated by fractional crystallization from acetone, or preferably,methanol or ethanol.

Mixtures of isomeric sulfonylbenzimidazole ester compounds can beseparated by selective hydrolysis of the more labile ester groups. Forexample, a mixture of ethyl1-diethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate isomers canbe hydrolyzed in aqueous potassium hydroxide. The insoluble unreacted6-isomer is separated by filtration. The basic aqueous filtrate containspredominantly potassium1-diethylaminosulfonyl-2-amino-5-benzimidazolecarboxylate and a smallamount of the 6-isomer salt. The filtrate is neutralized with diluteacid whereupon 1-diethylaminosulfonyl-2-amino-5-benzimidazolecarboxylicacid precipitates and is recovered. Ester hydrolysates bearing aminogroups in the 2-position should be precipitated in the pH range 5.0 to7.0.

The sulfonylbenzimidazole carboxylic acid compounds can be reconvertedto the esters of primary or secondary alcohols by reaction with thionylchloride in the presence of such carbinols as are used as the reactionmedium. Esters other than the esters of tertiary carbinols can also beprepared from the corresponding 5(6)-sulfonylbenzimidazolecarboxylicacids by reaction with molar equivalents of a primary or secondary C₁-C₈ alkyl carbinol, a C₃ -C₇ cycloalkyl alcohol, a C₃ -C₇cycloalkylmethanol, a 1-(C₃ -C₇ cycloalkyl)ethanol, allyl alcohol,propargyl alcohol, benzyl alcohol, α-methylbenzyl alcohol or phenol and1,1'-carbonyldiimidazole in the presence of a trace of carbinol anion.Preferred esters can be prepared by reacting the appropriatesulfonylbenzimidazolecarboxylic acid with propanol, isopropanol, t-butylalcohol, neopenty alcohol, cyclobutanol, cyclohexanol or1-(cyclopropyl)ethanol (α-methylcyclopropylmethanol) in the presence of1,1'-carbonyldiimidazole as described above. Thesulfonylbenzimidazolecarboxylic acids required are available from thecorresponding ethyl ester precursors by basic hydrolysis. Similarly, theN-substituted sulfonylbenzimidazolecarboxamide compounds can be preparedby reacting the same sulfonylbenzimidazole-carboxylic acids with a molarequivalent of a C₁ -C₄ alkylamine or a C₁ -C₄ alkoxyamine and1,1'-carbonyldiimidazole in dimethylformamide. When the corresponding2-acetamido sulfonylbenzimidazolecarboxylic acid is employed as areactant, the 2-amino ester or amide product can be obtained by basichydrolysis of the 2-acetyl group after esterification or amidation. Forexample, when1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid isreacted with one equivalent of isopropylamine or methoxyamine and1,1'-carbonyldiimidazole in dimethylformamide, the products arerespectively1-dimethylaminosulfonyl-2-amino-5(6)-N-isopropylbenzimidazolecarboxamideor1-dimethylaminosulfonyl-2-amino-5(6)-N-methoxybenzimidazolecarboxamide.Primary amides can be obtained when a5(6)-sulfonylbenzimidazolecarboxylic acid is reacted with ammonia and1,1'-carbonyldiimidazole.

Preferably, the sulfonyl benzimidazole compounds of Formula I wherein R₃is an ester or amide group are prepared by reacting a benzimidazolecompound (Formula II wherein R₃ is an amide or ester group) with asulfonyl chloride R₁ SO₂ Cl as described previously.

To prepare compounds in which R³ is hydrazinocarbonyl, the ethyl estersof the sulfonylbenzimidazolecarboxylic acids or isomeric mixturesthereof can be reacted with hydrazine in a carbinol solvent to yield thecorresponding hydrazides. For example, ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate can berefluxed with hydrazine hydrate in methanol to provide1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide. The hydrazide compounds or isomeric mixtures thereof areuseful for preparing the corresponding sulfonylbenzimidazolecarboxamidecompounds by cleavage of the hydrazide function with Raney nickel.1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide can be refluxed with Raney nickel in ethanol to provide1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxamide. Amidemixtures are separated by fractional crystallization.

The 5(6)-hydroxymethyl sulfonylbenzimidazole compounds (Formula I, R₃ is--CH₂ OH) can be prepared in several ways. The ethyl esters of the1-sulfonyl-2-substituted-5(6)-benzimidazolecarboxylic acids can bereduced chemically to provide the corresponding hydroxymethyl compounds.For example, ethyl1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate can bereduced with sodium bis(2-methoxyethoxy)-aluminum hydride intetrahydrofuran to provide1-dimethylaminosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole. Asuperior method reacts the sulfonyl chloride, R₁ SO₂ Cl, with theappropriate 2-substituted-5(6)-hydroxymethylbenzimidazole. The required5(6)-hydroxymethylbenzimidazole reactant can be prepared from thecorresponding ethyl 2-substituted-5(6)-benzimidazolecarboxylic acid byreduction with sodium bis(2-methoxyethoxy)-aluminum hydride in anaprotic solvent as described above. The preferred method for preparinglarge quantities of the hydroxymethyl sulfonyl benzimidazoleintermediates begins with 4-chloro-3-nitrobenzyl alcohol. The benzylalcohol is ammoniated to give 4-amino-3-nitrobenzyl alcohol. The nitroalcohol is hydrogenated catalytically to give4-hydroxymethyl-o-phenylenediamine. The phenylenediamine is then ringclosed to provide the desired2-substituted-5(6)-hydroxymethylbenzimidazole intermediate bycyclization methods known to the benzimidazole art.

Generally, the sulfonylbenzimidazole carboxylic acid compounds and theirhydrazides are useful only as intermediates which can be converted tothe corresponding ester or carboxamide compounds. However, some haveutility as antiviral agents; e.g.,1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylic acid inhibitsPolio I virus at 100 mcg./ml. (see Table I).

The required benzimidazole ester reactants (Formula II wherein R₃ is anester group) can be prepared from the appropriate o-phenylenediamineesters by methods known to the benzimidazole art. For example,3,4-dinitrobenzoic acid can be reacted with oxalyl chloride and pyridinein benzene to provide the corresponding 3,4-dinitrobenzoyl chloride.This acid chloride is reacted with an appropriate carbinol; i.e., astraight or branched chain aliphatic alcohol of one to eight carbonatoms, allyl alcohol, propargyl alcohol, a C₃ -C₇ cycloalkyl alcohol, a(C₃ -C₇ cycloalkyl)methanol, a 1-(C₃ -C₇ cycloalkyl)ethanol, benzylalcohol, α-methylbenzyl alcohol or phenol, in benzene with an acidscavanger such as pyridine to provide the corresponding ester. Theappropriate 3,4-dinitrobenzoic acid ester is then hydrogenated at 60 psiin the presence of a catalyst such as Raney nickel orpalladium-on-carbon to provide the corresponding o-phenylenediamineester. Cyclization of an o-phenylenediamine ester thus obtained withcyanogen bromide yields the 2-aminobenzimidazole esters (II where R³ isan ester group).

An alternative method for the preparation of o-phenylenediamine estersbegins with 3-nitro-4-chlorobenzoic acid instead of 3,4-dinitrobenzoicacid. Reaction of 3-nitro-4-chlorobenzoic acid as above with oxalylchloride and pyridine yields 3-nitro-4-chlorobenzoyl chloride. Theappropriate 3-nitro-4-chlorobenzoic acid ester is then prepared from theacid chloride as previously described. The 3-nitro-4-chlorobenzoic acidester is next reacted with dibenzylamine in dimethylformamide atelevated temperatures to give the corresponding3-nitro-4-dibenzylaminobenzoic acid ester. At this point the nitrodibenzyl ester is hydrogenated catalytically with Raney nickel forexample, with concomitant debenzylation and reduction of the nitro groupto provide the corresponding o-phenylenediamine ester. As before, theo-phenylenediamine ester is cyclized by methods known to thebenzimidazole art to provide the required benzimidazole ester reactants.

The required benzimidazole reactants represented by Formula II, whereinR₃ is an amide group, can be prepared from the appropriateo-phenylenediamine amides by known cyclization methods as describedabove. The o-phenylenediamine amides can be prepared by reacting3,4-dinitrobenzoyl chloride or 3-nitro-4-chlorobenzoyl chloridedescribed above with a molar equivalent of a C₁ -C₄ alkylamine or a C₁-C₄ alkoxyamine in the presence of an acid scavanger in an inertsolvent. The resulting N-alkoxy or N-alkyl amides of 3,4-dinitrobenzoicacid can be hydrogenated catalytically to provide the correspondingcarboxamido o-phenylenediamines. The N-alkoxy or N-alkyl amides of3-nitro-4-chlorobenzoic acid can be reacted with dibenzylamine indimethylformamide at elevated temperatures to give the corresponding3-nitro-4-dibenzylaminobenzoic acid amides. The nitro dibenzyl esterscan then be hydrogenated catalytically with Raney nickel for example,with concomitant debenzylation and reduction of the nitro group toprovide the corresponding o-phenylenediamine amides. The preparation ofa variety of benzimidazoles from o-phenylenediamines is well documentedin Weissberger's The Chemistry of Heterocyclic Compounds, Imidazole andIts Derivatives (Interscience Publisher Co., New York, 1953).

Other phenylenediamines useful to prepare the required startingmaterials of Formula II are prepared as follows:

3-Nitro-4-chlorobenzotrifluoride can be ammoniated and reduced toprovide 3,4-diaminobenzotrifluoride.

2-(3,4-Diaminophenyl)acetic acid can be prepared by acetylation of2-(4-aminophenyl)acetonitrile with acetic anhydride in pyridine. The2-(4-acetamidophenyl)acetonitrile product as nitrated in aceticanhydride to provide 2-(3-nitro-4-acetamidophenyl)acetonitrile. Thenitrile is hydrolyzed with concentrated hydrochloric acid to give2-(3-nitro-4-aminophenyl)acetic acid after neutralization. The nitroacid is then hydrogenated at 60 psi at room temperature overpalladium-on-carbon to yield 2-(3,4-diaminophenyl)acetic acid. The acidcan be esterified with C₁ -C₈ carbinols in the presence of acidcatalysts to yield starting materials according to II in which R³ is anester group. Similarly, the preparation of2-(3,4-diaminophenyl)propionic acid begins with2-(4-aminophenyl)propionitrile as described above for the preparation ofthe diaminophenylacetic acid.

4-Cyano-o-phenylenediamine can be prepared from 4-aminobenzonitrile by(a) acetylation to provide 4-acetamidobenzonitrile, (b) nitration toyield 3-nitro-4-acetamidobenzonitrile, (c) cleavage of the acetyl groupwith PCl₅ in pyridine to give 3-nitro-4-aminobenzonitrile and (d)hydrogenation of the nitro group at 60 psi with Raney nickel to provide3,4-diaminobenzonitrile(4-cyano-o-phenylenediamine).

4-Methylsulfonyl-o-phenylenediamine can be prepared by nitrating(4-chlorophenyl) methyl sulfone to yield (3-nitro-4-chlorophenyl) methylsulfone. The chloro group is ammoniated to give (3-nitro-4-aminophenyl)methyl sulfone. The nitro sulfone can then be hydrogenated withRuthenium-on-carbon to provide 4-methylsulfonyl-o-phenylenediamine.

The required benzimidazole reactants (II) are prepared by cyclizing theappropriate o-phenylenediamine compounds with cyanogen bromide asdescribed by Buttle, et al., Bio Chem. J. 32, 1101 (1938) and BritishPat. No. 551,524. Ethyl 2-amino-5-benzimidazolecarboxylate is describedby Paget, et al., J. Med. Chem., 12, 1010 (1969). Illustrative of suchbenzimidazole compounds which can be reacted with the appropriatesulfonyl chlorides are the 2-aminobenzimidazole reactants (II) which aresubstituted in the 5(6) position by C₁ -C₈ alkoxycarbonyl,allyloxycarbonyl, propargyloxycarbonyl, (C₃ -C₇ cycloalkyl)oxycarbonyl,(C₃ -C₇ cycloalkyl)methyloxycarbonyl, 1-(C₃ -C₇cycloalkyl)ethyloxycarbonyl, benzyloxycarbonyl, α-methyloxycarbonyl,phenoxycarbonyl, C₁ -C₈ alkoxycarbonylmethyl, 1-(C₁ -C₈alkkoxycarbonyl)ethyl, carboxamido, cyano, methylsulfonyl,trifluoromethyl, and the like.

Among the sulfonyl chloride compounds which are required to react withthe starting materials of Formula II to prepare the compounds of thisinvention (I), methanesulfonyl chloride (mesylchloride),isopropylsulfonyl chloride, dimethylsulfamoyl chloride, benzenesulfonylchloride, 2-thiophenesulfonyl chloride, and2-acetamido-4-methyl-5-thiazolesulfonyl chloride are commerciallyavailable. The preparation of 3-thiophenesulfonyl chloride and 2 (or3)-furansulfonyl chloride is described by Arcoria et al. [see J. Org.Chem., 39 1689 and 3595 (1974)]. 2-Thiazolesulfonyl chloride,2-thiadiazolesulfonyl chloride, 2-methyl-5-thiadiazolesulfonyl chlorideand 2-methylamino-5-thiadiazolesulfonyl chloride are available from2-thiazolethiol, 2-thiadiazolethiol, 2-methyl-5-thiadiazolethiol and2-methylamino-5-thiadiazolethiol respectively by oxidation of the thiolfunction with bromine or chlorine in aqueous solution. Other C₁ -C₅alkyl and C₃ -C₇ cycloalkyl sulfonyl chlorides can be prepared by thechlorination of the appropriate alkyl thiol or by reacting sulfurylchloride with sodium alkyl sulfonates derived from the correspondingcarbinols and sulfuric acid. The N,N-dialkylsulfamoyl chlorides can beprepared as described by Bindely et al., J. Am. Chem. Soc. 61, 3250(1939), by reacting the salt of a secondary amine (R₄ R₅ NH) withsulfuryl chloride. Alternatively, they can be prepared by reacting achloramine compound of the formula

    R.sub.4 R.sub.5 N--Cl

with a sulfur dioxide at a temperature of -5° to 30° C. The chloraminecompounds are prepared by reacting the corresponding secondary amines(R₄ R₅ NH) with antimony pentachloride, sodium hypochlorite or sulfurylchloride.

Illustrative of other sulfonyl chlorides which can be reacted with thebenzimidazole reactants (II) are ethyl-, propyl-, isopropyl-, butyl-,isobutyl- sec-butyl, tert-butyl-, amyl, isoamyl-, sec-isoamyl-, andtert-amylsulfonyl chloride.

Yet other sulfamoyl chlorides which can be employed are diethyl-,dipropyl-, N-methyl-N-ethyl-, N-methyl-N-propyl-, N-ethyl-N-propyl-,N-methyl-N-isopropyl-, N-ethyl-N-isopropyl, N-propyl-N-isopropyl-,diisopropyl-, pyrrolidino-, piperidino-, and morpholinosulfamoylchloride.

For consistency in nomenclature, the sulfonylbenzimidazole compoundswill be named as sulfonyl derivatives. For example, the product of thereaction of dimethylsulfamoyl chloride and ethyl2-amino-5-benzimidazolecarboxylate is named ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate ratherthan ethyl 1-dimethylsulfamoyl-2-amino-5(6)-benzimidazolecarboxylate.The compounds of the invention were tested by the following methods.

Test Methods

African green monkey kidney cells (BSC-1) or Hela cells (5-3) were grownin 25 cc. Falcon flasks at 37° C. in medium 199 with 5 percentinactivated fetal bovine serum (FBS), penicillin (150 units 1 ml.) andstreptomycin (150 mcg./ml.). When confluent monolayers were formed, thesupernatant growth medium was removed and 0.3 ml. of an appropriatedilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) wasadded to each flask. After adsorption for one hour at room temperature,the virus infected cell sheet was overlaid with a medium comprising onepart of 1 percent Ionagar No. 2 and one part double strength medium 199with FBS, penicillin, and streptomycin which contains drug atconcentrations of 100, 50, 25, 12, 6, 3, 0.75 and 0 micrograms permilliliter (mcg./ml.). The flask containing no drug served as thecontrol for the test. The stock solutions of sulfonylbenzimidazolecompounds were made up in dimethylsulfoxide at a concentration of 10⁴mcg./ml. The flasks were incubated for 72 hours at 37° C. for polio,Coxsackie, echo, and Mengo virus and 120 hours at 32° C. for rhinovirus.Plaques were seen in those areas where the virus infected and reproducedin the cells. A solution of 10 percent formalin and 2 percent sodiumacetate was added to each flask to inactivate the virus and fix the cellsheet to the surface of the flask. The virus plaques, irrespective ofsize, were counted after straining the surrounding cell areas withcrystal violet. The plaque count was compared to the control count ateach drug concentration. The activity of the test compound was expressedas percentage plaque reduction, or percent inhibition. Alternatively,the drug concentration which inhibits plaque formation by 50 percentindicated by the symbol I₅₀ can be used as a measure of activity.

Test results are expressed in terms of Polio virus type I inhibitionbecause the virus is easy to grow and consistent test results areobtained. However, the activity of the preferred compounds was confirmedagainst other virus cultures. For example, ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate at 3.0mcg./ml. inhibits Coxsackie (A9, A21, B5), echovirus (strains 1-4),Mengo, rhinovirus (25 strains) and Polio (type I, II, III). Test resultsfor various sulfonylbenzimidazole compounds are summarized in Tables I,II and III below.

In Table I, columns 1-3 give the substituent groups which define theparticular sulfonylbenzimidazole compound of Formula I. Columns 4-11give the percentage plaque reduction for the specified drugconcentrations.

In Table II, column 1 names the particular ester of1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid.Columns 2-4 give the drug concentrations of that particular ester whichinhibits virus plaque formation by 50 percent (I₅₀) for Polio I,rhinovirus strain 3, and Coxsackie virus strain A21 respectively.

In Table III, column 1 names the particular ester of1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid.Columns 2-4 give the drug concentration of that particular ester whichinhibits virus plaque formation by 50 percent (I₅₀) for Polio I,rhinovirus strain 3 and Coxsackie virus strain A21 respectively.

                                      TABLE 1                                     __________________________________________________________________________    Percent Plaque Reduction (Polio I)                                            Drug Concentration (mcg./ml.)                                                 R.sup.1                                                                             R.sup.2                                                                          R.sup.3                                                                              100                                                                              50 25  12  6   3   1.5                                                                              0.75                                 __________________________________________________________________________    Me.sub.2 N                                                                          H  6-CO.sub.2 Et                                                                           64 0   0   0   0                                           Me.sub.2 N                                                                          CH.sub.3                                                                         6-CO.sub.2 Et                                                                           90 80  50  22  0                                           Me.sub.2 N                                                                          NH.sub.2                                                                         5-CO.sub.2 Et                                                                              100 98  72  37  25 0                                    Me.sub.2 N                                                                          NH.sub.2                                                                         6-CO.sub.2 Et                                                                           100                                                                              100 100 100 100 96 52                                   methyl                                                                              NH.sub.2                                                                         6-CO.sub.2 Et    87  51  24  0  0                                    isopropyl                                                                           NH.sub.2                                                                         6-CO.sub.2 Et    100 100 98  54 24                                   Me.sub.2 N                                                                          NH.sub.2                                                                         5-CF.sub.3                                                                           62 64 64  61  51  0                                           pyrrolidino                                                                         NH.sub.2                                                                         5(6)-CO.sub.2 Et*                                                                       100                                                                              100 100 99  63                                          piperidino                                                                          NH.sub.2                                                                         5(6)-CO.sub.2 Et*                                                                       toxic                                                                            toxic                                                                             100 100 3                                           morpholino                                                                          NH.sub.2                                                                         5(6)-CO.sub.2 Et*                                                                       100                                                                              99  86  3   0                                           Me.sub.2 N                                                                          NH.sub.2                                                                         6-CO.sub.2 Me        100 97  60 35                                   Me.sub.2 N                                                                          NH.sub.2                                                                         6-CO.sub.2 C.sub.4 H.sub.9                                                                         100 98  63 28                                   Me(Et)N                                                                             NH.sub.2                                                                         6-CO.sub.2 Et    100 100 100 83 51                                   Me(Pr)N                                                                             NH.sub.2                                                                         6-CO.sub.2 Et    100 100 90  52 35                                   Et.sub.2 N                                                                          NH.sub.2                                                                         6-CO.sub.2 Et    100 100 87  43 25                                   Me.sub.2 N                                                                          NH.sub.2                                                                         6-COOH 50    34      23  17                                          Me.sub.2 N                                                                          NH.sub.2                                                                         5-CONH.sub.2                                                                         55 32 30  25  23  8                                           Me.sub.2 N                                                                          NH.sub.2                                                                         6-CONH.sub.2                                                                         100                                                                              100                                                                              100 78  43  36  27                                      Me.sub.2 N                                                                          NH.sub.2                                                                         5-CONHEt                                                                             97 54 21  7                                                   Me.sub.2 N                                                                          NH.sub.2                                                                         6-CONHEt                                                                             100                                                                              100                                                                              100 99  80  40  9                                       __________________________________________________________________________     *Isomeric mixtures                                                       

The drug concentration of various esters other than the ethyl esterswhich inhibit virus plaque formation by 50 percent (I₅₀) are summarizedin Tables II and III.

                  Table II                                                        ______________________________________                                        Virus Inhibition (I.sub.50) of                                                Esters of 1-Dimethylaminosulfonyl-2-                                          Amino-5(6)-Benzimidazolecarboxylic Acids                                                  I.sub.50 (mcg/ml)                                                 Ester*        Polio I   Rhino 3   Cox A21                                     ______________________________________                                        (6)methyl     3         0.75      3                                           propyl        1.5       3         1.5                                         (6)-isopropyl 0.35      0.75      1.5                                         allyl         3-6                                                             propargyl     3-6                                                             butyl         3         0.75      3                                           (5)-isobutyl  3         3-6       3                                           (6)-neopentyl 0.75      0.75      1.5                                         (5)-neopentyl 3                                                               octyl         50                                                              (6)cyclohexyl 0.35      1.5       0.75                                        cyclohexylmethyl                                                                            3-6       1.5                                                   benzyl        6                                                               α-methylbenzyl                                                                        3                                                               ______________________________________                                         *The isomer is indicated by number; otherwise the ester is an isomeric        mixture. mcg/ml is the drug concentration in micrograms per milliliter.  

                  Table III.                                                      ______________________________________                                        Virus Inhibition (I.sub.50) of                                                Esters of 1-Dimethylaminosulfonyl-2-Acetamido-                                5(6)-Benzimidazolecarboxylic Acid                                                          I.sub.50 (mcg/ml)                                                Ester*         Polio I   Rhino 3   Cox A21                                    ______________________________________                                        isopropyl      0.75                                                           (5)-isopropyl  3                                                              (6)-isobutyl   0.75      <3        0.75-1.5                                   neopentyl      1.5-3                                                          sec-butyl      0.75                                                           (5)-cyclopropylmethyl                                                                        6                                                              (6)-cyclopropylmethyl                                                                        0.75-1.5            1.5                                        cyclohexylmethyl                                                                             3                   1.5-3                                      3-methylcyclohexyl-                                                           methyl         3                                                              1-(cyclopropyl)ethyl                                                                         0.75      <5        1.5                                        cyclobutyl     0.35      <5        1.5                                        cyclohexyl     1.5                                                            (6)-phenyl     3-6                                                            ______________________________________                                         *The isomer is indicated by number otherwise the ester is an isomeric         mixture. mcg/ml is the drug concentration in micrograms per milliliter.  

The sulfonylbenzimidazole compounds were tested as pure compounds and asisomer mixtures. Both isomers inhibit virus growth, the 6-isomergenerally being more active than the 5-isomer. For example, ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate inhibitedPolio I virus completely at a concentration as low as 3.0 mcg./ml. The5-isomer inhibited completely at a concentration of 12.0 mcg./ml.

Among the preferred compounds of the invention are the 1-(C₁-C₅)alkylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate esters.Especially preferred are the1-(aminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate esters. Mostpreferred are the ethyl, propyl, isopropyl, isopropyl, t-butyl,neopentyl, cyclobutyl, cyclohexyl and 1-(cyclopropyl)ethyl esters of the1-(N,N-dialkylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylic acids.The 6-isomers are preferred over 5-isomers.

Compounds coming within the scope of the above formula are able tosuppress the growth of certain viruses when added to a medium in whichthe virus is growing. The compounds of the invention can therefore beused in aqueous solution, preferably with a surfactant, to decontaminatesurfaces on which polio, Coxsackie, rhinovirus and other viruses arepresent, such surfaces including hospital glassware, hospital workingsurfaces and similar areas in the preparation of food.

Furthermore, the compounds can be orally administered to warm-bloodedanimals and humans in a dose of 1 to 300 mg./kg. of animal body weight.The administration can be repeated periodically as needed. In accordancewith general practice, the antiviral compound can be administered everyfour to six hours.

Preferably, the compounds to be employed in accordance with the presentinvention are employed in combination with one or more adjuvants suitedto the particular route of administration. Thus, in the case of oraladministration, the compound is modified with pharmaceutical diluents orcarriers such as lactose, sucrose, starch powder, cellulose, talc,magnesium stearate, magnesium oxide, calcium sulfate, acacia powder,gelatin, sodium alginate, sodium benzoate and stearic acid. Suchcompositions can be formulated as tablets or enclosed in capsules forconvenient administration. In addition, the compounds can beadministered parenterally.

The compounds can also be mixed with a liquid and administered as nosedrops or intranasal spray.

Illustrative of the esters and amides of thesulfonylbenzimidazolecarboxylic acid compounds provided by thisinvention are the following:

1-Cyclopropylsulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,cyclopropyl ester,

1-(2-Furan)sulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cyclopentyl ester,

1-(2-Thiophene)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylicacid, cyclohexyl ester,

1-(2-Thiazole)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,cycloheptyl ester,

1-(2-Thiazole)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,cycloheptyl ester,

1-Cyclopentylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cyclopropylmethyl ester,

1-[2-(1,3,4-thiadiazole)sulfonyl]-2-amino-5(6)benzimidazolecarboxylicacid, cyclobutylmethyl ester,

1-Cyclohexylsulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,cyclopentylmethyl ester,

1-Isopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cycloheptylmethyl ester,

1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-(cyclopropyl)ethyl ester,

1-Piperidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,1-(cyclobutyl)ethyl ester,

1-Pyrrolidinosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-(cyclopentyl)ethyl ester,

1-Diethylaminosulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,1-(cyclohexyl)ethyl ester,

1-Dipropylaminosulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,1-(cycloheptyl)ethyl ester,

1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,2-methylcyclohexyl ester,

1-Diethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,3-methylcyclohexyl ester,

Isopropyl 1-(2-furan)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

Neopentyl 1-(2-thiazole)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

Cyclohexyl1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

1-(2-Methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-formamido-5(6)-benzimidazolecarboxylicacid, 1-(cyclopropyl)ethyl ester,

Neopentyl1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

Isopropyl 1-isopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

Neopentyl 1-benzenesulfonyl-2-formamido-5(6)-benzimidazolecarboxylate,

Cyclobutyl1-(2-thiophene)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

Cyclohexyl 1-(2-thiozole)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-(cyclopropyl)ethyl ester,

Neopentyl 1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

Cyclobutyl1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate,

Isopropyl1-(N-methyl-N-propylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylate,

Cyclohexyl1-dipropylaminosulfonyl-2-formamido-5(6)-benzimidazolecarboxylate,

Isopropyl 1-pyrrolidinosulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

Neopentyl1-piperidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

Cyclobutyl1-piperidinosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

1-Isopropylsulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,4-methylcyclohexyl ester,

1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-methylcyclohexyl ester,

1-Dimethylaminosulfonyl-2-acetamido-5(6)-N-methylbenzimidazolecarboxamide,

1-(2-Methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-formamido-5(6)-N-ethylbenzimidazolecarboxamide.

1-Pyrrolidinosulfonyl-2-propionamido-5(6)-N-propylbenzimidazolecarboxamide,

1-Morpholinosulfonyl-2-acetamido-5(6)-N-isopropylbenzimidazolecarboxamide,

1-Dipropylaminosulfonyl-2-amino-5(6)-N-butylbenzimidazolecarboxylamide,

1-[(3-Furan)sulfonyl]-2-formamido-5(6)-N-sec-butylbenzimidazolecarboxamide,

1-Pyrrolidinosulfonyl-2-propionamido-5(6)-N-isobutylbenzimidazolecarboxamide,

1-Phenylsulfonyl-2-amino-5(6)-N-tert-butylbenzimidazolecarboxamide,

1-Butylsulfonyl-2-acetamido-5(6)-N-methoxybenzimidazolecarboxamide,

1-Isobutylsulfonyl-2-formamido-5(6)-N-ethoxybenzimidazolecarboxamide,

1-Diisopropylaminosulfonyl-2-propionamido-5(6)-N-propoxybenzimidazolecarboxamide,

1-Diethylaminosulfonyl-2-acetamido-5(6)-N-isopropoxybenzimidazolecarboxamide,

1-Diethylaminosulfonyl-2-amino-5(6)-N-butoxybenzimidazolecarboxamide,

1-Piperidinosulfonyl-2-amino-5(6)-N-isobutoxybenzimidazolecarboxamide,

1-[(5-Methyl-1,3,4-thiadiazol-5-yl)sulfonyl]-2-formamido-5(6)-N-sec-butoxybenzimidazolecarboxamide,and

1-Cyclopropylsulfonyl-2-acetamido-5(6)-N-tert-butoxybenzimidazolecarboxamide.

Further illustrative of the sulfonylbenzimidazole compounds provided bythis invention are the following:

1-methylsulfonyl-2-amino-5(6)-cyanobenzimidazole,

1-ethylsulfonyl-2-amino-5(6)-methylsulfonylbenzimidazole,

1-propylsulfonyl-2-amino-5(6)-trifluoromethylbenzimidazole,

1-isopropylsulfonyl-2-formamido-5(6)-methylsulfonylbenzimidazole,

1-butylsulfonyl-2-propionamido-5(6)-trifluoromethylbenzimidazole,

1-isobutylsulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-(sec-butylsulfonyl)-2-amino-5(6)-benzimidazolecarboxamide,

1-(tert-butylsulfonyl)-2-formamido-5(6)-benzimidazolecarboxylic acidhydrazide,

neopentyl1-cyclopentylsulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

1-morpholinosulfonyl-2-amino-5(6)-N-propylbenzimidazolecarboxamide,

propargyl1-piperidinosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-N-methoxybenzimidazolecarboxamide,

1-dipropylaminosulfonyl-2-acetamido-5(6)-N-ethylbenzimidazolecarboxamide,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylicacid, α-methylbenzyl ester,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-N-isopropoxybenzimidazolecarboxamido,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-piperidinosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-hydroxymethylbenzimidazole,

neopentyl1-isopropylsulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

propargyl 1-cyclohexylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, phenyl ester,

1-cyclopropylsulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,phenyl ester,

1-piperidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,phenyl ester,

1-amylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,

1-isoamylsulfonyl-2-formamido-5(6)-benzimidazole,

1-(sec-isoamylsulfonyl)-2-amino-5(6)-methylsulfonylbenzimidazole,

1-(tert-amylsulfonyl)-2-propionamido-5(6)-trifluoromethylbenzimidazole,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-methylsulfonylbenzimidazole,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-trifluoromethylbenzimidazole,

1-(N-methyl-N-isopropylaminosulfonyl)-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-diethylaminosulfonyl-2-amino-5(6)-methylsulfonylbenzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-trifluoromethylbenzimidazole

1-(N-ethyl-N-isopropylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxamide,

1-dipropylaminosulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(N-propyl-N-isopropylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylicacid,

1-diisopropylaminosulfonyl-2-amino-5(6)-cyanobenzimidazole,

1-benzenesulfonyl-2-amino-5(6)-methylsulfonylbenzimidazole,

1-pyrrolidinosulfonyl-2-formamido-5(6)-trifluoromethylbenzimidazole,

1-benzenesulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, phenylester,

cyclobutyl1-(2-thiazole)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-formamido-5(6)-hydroxymethylbenzimidazole,

1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-N-butylbenzimidazolecarboxamide,

1-cyclopropylsulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-(3-furan)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,phenyl ester,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylicacid, 1-(cyclopropyl)ethyl ester,

1-(2-thiophene)sulfonyl-2-acetamido-5(6)-N-butoxybenzimidazolecarboxamide,

1-diethylaminosulfonyl-2-amino-5(6)-N-butylbenzimidazolecarboxamide,

neopentyl1-cyclohexylsulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

allyl1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

propargyl1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-formamido-5(6)-N-propylbenzimidazolecarboxamide,

1-isopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cyclobutylmethyl ester,

1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,1-(cyclohexyl)ethyl ester,

1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylicacid, α-methylbenzyl ester,

1-cycloheptylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-(cycloheptyl)ethyl ester,

1-piperidinosulfonyl-2-propionamido-5(6)-hydroxymethylbenzimidazole,

1-morpholinosulfonyl-2-amino-5(6)-methylsulfonylbenzimidazole,

1-methylsulfonyl-2-formamido-5(6)-benzimidazolecarboxylic acid,2,2,4-trimethyl-1-pentyl ester,

1-ethylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, isooctylester,

1-propylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, 2-ethylhexylester,

1-isopropylsulfonyl-2-propionamido-5(6)-benzimidazolecarboxylic acid,2-octyl ester,

1-butylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, 2-heptylester,

1-isobutylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, octylester,

1-(sec-butylsulfonyl)-2-amino-5(6)-benzimidazolecarboxylic acid, heptylester,

1-(tert-butylsulfonyl)-2-formamido-5(6)-benzimidazolecarboxylic acid,heptyl ester,

1-amylsulfonyl-2-propionamido-5(6)-benzimidazolecarboxylic acid, octylester,

1-isoamylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,4-methyl-2-pentyl ester,

1-(1,2-dimethylpropylsulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, isooctyl ester,

1-(tert-amylsulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylic acid,propyl ester,

propargyl1-pyrrolidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

cyclobutyl1-(N-methyl-N-isopropylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylate,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-N-isopropylbenzimidazolecarboxamide,

1-(2-thiophene)sulfonyl-2-amino-5(6)-N-isopropoxybenzimidazolecarboxamide,

neopentyl1-(2-thiazole)sulfonyl-2-formamido-5(6)-benzimidazolecarboxylate,

allyl 1-piperidinosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

neopentyl1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

1-(N-methyl-N-propylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylate,1-(cyclobutyl)ethyl ester,

1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,phenyl ester,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylicacid, phenyl ester,

1-isopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, phenylester,

1-cyclopropylsulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,1-(cyclopropyl)ethyl ester,

propargyl1-dipropylaminosulfonyl-2-propionamido-5(6)-benzimidazolecarboxylate,

1-(2-furan)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,cyclopropylmethyl ester,

1-benzenesulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cyclopropylmethyl ester,

cyclobutyl1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate,

1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,phenyl ester,

1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,2,2,4-trimethyl-1-pentyl ester,

1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, isopropyl ester,

1-(N-methyl-N-propylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, butyl ester,

1-(N-methyl-N-isopropylaminosulfonyl)-2-formamido-5(6)-benzimidazolecarboxylicacid, isobutyl ester,

1-diethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, hexylester,

1-(N-ethyl-N-propylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, 2-heptyl ester,

1-(N-ethyl-N-isopropylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, methyl ester,

1-dipropylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,isobutyl ester,

1-(N-propyl-N-isopropylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylicacid, propyl ester,

1-diisopropylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,2-ethylhexyl ester,

1-benzenesulfonyl-2-propionamido-5(6)-benzimidazolecarboxylic acid,butyl ester,

1-pyrrolidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,2-octyl ester,

1-piperidinosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid, heptylester,

1-morpholinosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,2-ethyl-1-butyl ester,

neopentyl1-(1,3,5-thiadiazol-2-yl)sulfonyl-2-formamido-5(6)-benzimidazolecarboxylate,

1-benzenesulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,cycloheptylmethyl ester,

neopentyl1-morpholinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

cyclohexyl 1-cyclohexylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

benzyl1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

allyl1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

allyl 1-isopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

propargyl 1-benzenesulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

cyclobutyl1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-formamido-5(6)-benzimidazolecarboxylate,

neopentyl1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

1-pyrrolidinosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acid,1-(cyclopropyl)ethyl ester,

benzyl1-(2-thiophene)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

propargyl1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

isopropyl 1-(3-furan)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate,

1-cyclobutylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acid,1-(cyclopropyl)ethyl ester,

cyclobutyl1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate,

2-(1-methylsulfonyl-2-H-benzimidazole-5-yl)acetic acid,4-methyl-2-pentyl ester.

2-(1-benzenesulfonyl-2-methylbenzimidazol-5-yl)acetic acid,2-methyl-1-pentyl ester,

2-(1-dimethylaminosulfonyl-2-acetamidobenzimidazol-5-yl)acetic acid,ethyl ester,

2-(1-morpholinosulfonyl-2-aminobenzimidazol-5-yl)acetic acid, tert-butylester,

2-(1-methylsulfonyl-2-H-benzimidazol-5-yl)propionic acid, methyl ester,

2-(1-benzenesulfonyl-2-aminobenzimidazol-5-yl)propionic acid, isopropylester,

2-(1-dimethylaminosulfonyl-2-acetamidobenzimidazol-5-yl)propionic acid,sec-butyl ester,

2-(1-pyrrolidinosulfonyl-2-methylaminobenzimidazol-5-yl)propionic acid,isooctyl ester,

2-(1-diisopropylaminosulfonyl-2-methylbenzimidazol-5-yl)propionic acid,2-ethylhexyl ester,

1-methylsulfonyl-2-acetamido-5(6)-cyanobenzimidazole,

1-benzenesulfonyl-2-formamido-5(6)-cyanobenzimidazole,

1-isopropylsulfonyl-2-acetamido-5(6)-cyanobenzimidazole,

1-dimethylaminosulfonyl-2-amino-5(6)-cyanobenzimidazole,

1-pyrrolidinosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-(N-ethyl-N-propylaminosulfonyl)-2-acetamido-5(6)-cyanobenzimidazole,

neopentyl1-(N-methyl-N-propylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylate,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-propionamido-5(6)-benzimidazolecarboxylicacid, α-methylbenzyl ester,

propargyl1-(N-methyl-N-isopropylaminosulfonyl)-2-acetamido-5(6)-benzimidazolecarboxylate,

1-cyclopropylsulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(2-thiophene)sulfonyl-2-formamido-5(6)-benzimidazolecarboxamide,

1-(N-ethyl-N-propylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxamide,

1-piperidinosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide,

1-benzenesulfonyl-2-acetamido-5(6)-N-ethoxybenzimidazolecarboxamide,

1-dimethylaminosulfonyl-2-amino-5(6)-N-isopropoxybenzimidazolecarboxamide,

1-(2-methyl-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylicacid hydrazide,

1-(2-acetamido-4-methylthiazol-5-yl)-2-amino-5(6)-benzimidazolecarboxamide,

1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylicacid hydrazide,

1-dipropylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate, phenylester,

1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidhydrazide,

1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-acetamido-5(6)-benzimidazolecarboxylicacid hydrazide,

1-(1,3,4-thiadiazol-2-yl)sulfonyl-2-formamido-5(6)-benzimidazolecarboxylicacid, 1-(cyclopropyl)ethyl ester,

allyl 1-butylsulfonyl-2-amino-5(6)-benzimidazolecarboxylate,

1-benzenesulfonyl-2-amino-5(6)-cyanobenzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-benzenesulfonyl-2-acetamido-5(6)-trifluoromethylbenzimidazole,

1-benzenesulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole,

1-dimethylaminosulfonyl-2-acetamido-5(6)-hydroxymethylbenzimidazole, and

1-dimethylaminosulfonyl-2-acetamido-5(6)-trifluoromethylbenzimidazole.

The following examples further illustrate the preparation of thestarting materials, intermediates, and compounds of the invention.

EXAMPLE 1 Ethyl 3,4-Diaminobenzoate

One mole (152 g.) of 3,4-diaminobenzoic acid was stirred with 2 litersof ethanol in a Morton flask. Hydrogen chloride gas was passed throughthe stirred suspension for about 2 hours. As the gas was absorbed, theslurry became gel-like in character. Ethanol (500 ml.) was added to thereaction mixture to disperse the gel. The reaction mixture was refluxed24 hours. The mixture was filtered and the filtrate was evaporated todryness in vacuo. The filter cake and the filtrate residue weredissolved in 9 liters of water. The aqueous solution was made basic bythe addition of solid sodium carbonate. The product precipitated fromthe basic solution. The material was filtered and dried to yield 130grams of ethyl 3,4-diaminobenzoate.

EXAMPLE 2 Cyclohexyl 2-Amino-5(6)-Benzimidazolecarboxylate (A)Cyclohexyl 3-nitro-4-chlorobenzoate

Ten grams (0.05 mole) of 3-nitro-4-chlorobenzoic acid, 50 ml. ofbenzene, 13 g. (0.1 mole) of oxalyl chloride and 3 drops of pyridinewere stirred at room temperature for about one hour. The mixture waswarmed to 55° C. to obtain a homogeneous solution. The reaction mixturewas evaporated in vacuo to yield an oil. Under vacuum the oilcrystallized to yield 12 g. of 3-nitro-4-chlorobenzoyl chloride.

Twelve grams (0.055 mole) fo crude 3-nitro-4-chlorobenzoyl chloride wasdissolved in 200 ml. of benzene. Eight milliliters of pyridine wereadded to the reaction mixture. Six milliliters of cyclohexanol weredissolved in 50 ml. of benzene and the solution was added dropwise tothe acid chloride-pyridine mixture. The reaction mixture was refluxedfor 4 hours and filtered. The benzene filtrate was washed successivelywith dilute acid, dilute base and water. The washed benzene solution wasdried and evaporated in vacuo to yield 12.5 g (88 percent) of cyclohexyl3-nitro-4-chlorobenzoate, mp 57°-58° C.

Analysis C₁₃ H₂₄ ClNO₄ : MW 283.5. Calcd: C, 55.04; H, 4.97; N, 4.94.Found: C, 54.90; H, 5.15; N, 5.14.

(B) Cyclohexyl 3-nitro-4-dibenzylaminobenzoate

Two and eight-tenths grams (0.01 mole) of cyclohexyl3-nitro-4-chlorobenzoate, 4.4 ml. (0.022 mole) of dibenzylamine and 20ml. of dimethylformamide (DMF) were refluxed for six hours. The reactionmixture was evaporated in vacuo and the residue was diluted with 500 ml.of water. The aqueous mixture was extracted with ethyl acetate. Theethyl acetate solution was dried and evaporated in vacuo to give an oil.The oil was taken up in ether and filtered. The solution was evaporatedin vacuo to yield 4.2 g. (95 percent) of cyclohexyl3-nitro-4-dibenzylaminobenzoate as an oil.

(C) Cyclohexyl 2-Amino-5(6)-benzimidazolecarboxylate

One hundred grams (0.386 mole) of cyclohexyl3-nitro-4-dibenzylaminobenzoate were hydrogenated at 60° C. for 22 hourswith 25 g. of palladium-on-carbon in 875 ml. of 2B ethanol. The catalystwas filtered and the filtrate was evaporated in vacuo to leave an oil.The oil was taken up in ethyl acetate and filtered. Anhydrous HCl gaswas passed over the surface of the ethyl acetate solution with stirring.The precipitated o-phenylenediamine hydrochloride salt was collected andwashed with anhydrous ether to yield 24.3 g. of product. The salt wasdissolved in water and the pH of the aqueous solution was adjusted to7.00 with 1 N sodium hydroxide (130 ml.). Forth milliliters of methanoland 9 g. (0.0845 mole) of cyanogen bromide were added to the aqueoussolution. The reaction mixture was stirred overnight. The aqueousmixture was basified with 1 N sodium hydroxide and extracted with ethylacetate. The ethyl acetate extract was decolorized with carbon andfiltered. The ethyl acetate solution was evaporated in vacuo to yield 16g. (73 percent yield based on cyanogen bromide) of cyclohexyl2-amino-5(6)-benzimidazolecarboxylate as an oil.

EXAMPLE 3 t-Butyl1-(Dimethylsulfonylamino)-2-Amino-5(6)-Benzimidazolecarboxylate (A)t-Butyl 3,4-Dinitrobenzoate

Fifty-three grams (0.25 mole) of 3,4-dinitrobenzoic acid, 500 ml. ofbenzene, 65 g. (0.51 mole) of oxalyl chloride and 1 ml. of pyridine werereacted according to Example 2 (A), first paragraph, to provide3,4-dinitrobenzoyl chloride as a crude oil.

The crude 3,4-dinitrobenzoyl chloride, 500 ml. of benzene, 25 ml. ofpyridine and 22 g. (0.3 mole) of t-butyl alcohol were reacted as inExample 2 (A), second paragraph, to provide 33 g. (49 percent yield) oft-butyl 3,4-dinitrobenzoate.

Analysis C₁₁ H₁₂ N₂ O₆ : MW 268. Calcd: C, 49.26; H, 4.51; N, 10.44.Found: C, 48.95; H, 4.30; N, 10.14.

(B) t-Butyl 2-amino-5(6)-benzimidazolecarboxylate

Four and two-tenths grams (0.02 mole) of t-butyl 3,4-dinitrobenzoatewere hydrogenated in 95 ml. of ethanol with 1 g. of 5 percentpalladium-on-carbon for one hour at room temperature. The exothermicreaction reached a maximum temperature of 45° C. with a hydrogen uptakewhich was 85 percent of theoretical. The catalyst was filtered and thefiltrate was evaporated in vacuo to a residual oil. The crude t-butyl3,4-diaminobenzoate product (0.017 mole) was taken up in a mixture of 20ml. of methanol and 200 ml. of water. Cyanogen bromide, 1.8 g. (0.017mole), was reacted with the diamine ester according to the method ofExample 2(C) to yield 1.5 g. (38 percent yield) of t-butyl2-amino-5(6)-benzimidazolecarboxylate.

(C) t-Butyl1-(dimethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate

Three grams (0.013 mole) of t-butyl2-amino-5(6)-benzimidazolecarboxylate, 50 ml. of dimethoxyethane, 0.7 g.of 50 percent sodium hydride and 1.9 g. of dimethylsulfamoyl chloridewere refluxed for 3 hours. The reaction mixture was filtered and thefiltrate was evaporated to dryness in vacuo. The product residue wastreated with water and the mixture was extracted with ethyl acetate. Theextract was dried (Na₂ SO₄) and concentrated by boiling on the steambath until incipient crystallization. The ethyl acetate mixture wascooled in an ice bath and the crystalline product, t-butyl1-(dimethylaminosulfonyl)-2-amino-5(6)-benzimidazolecarboxylate, wasfiltered.

EXAMPLE 4 Butyl 2-Amino-5-Benzimidazolecarboxylate

Eleven grams (53 mmoles) of butyl 3,4-diaminobenzoate and 5.7 g. (53mmoles) of cyanogen bromide were stirred overnight in 300 ml. of water.The reaction mixture was neutralized with dilute base and was dilutedwith 600 ml. of water. The aqueous phase was extracted with ethylacetate. The extract was decolarized with carbon and the solvent wasevaporated to dryness in vacuo. The residue was triturated with ethylacetate to yield 11 g. of butyl 2-amino-5-benzimidazolecarboxylate, m.p.about 183°-185° C.

Analysis C₁₂ H₁₅ N₃ O₂ : MR 233. Calcd: C, 61.79; H, 6.48. Found: C,61.61; H, 6.63.

EXAMPLE 5 Ethyl 2-Methylamino-5-Benzimidazolecarboxylate

(A) Preparation of a mixture of Ethyl 3-amino-4-(3-methyl2-thioureido)benzoate and Ethyl4-amino-3-(3-methyl-2-thioureido)benzoate.

Twelve grams (0.1 mole) of ethyl 3,4-diaminobenzoate were dissolved in300 ml. of acetone with stirring. One tenth mole, 7.3 g., ofmethylisothiocyanate in acetone was added to the reaction mixture. Themixture was refluxed for 20 hours. After cooling, the mixture wasevaporated in dryness in vacuo. The residue was washed with ether andthe product was collected to yield 12 g. of the thiourea mixture. Theisomeric mixture was characterized by NMR and used in the followingstep.

(B) Preparation of Ethyl 2-methylamino-5-benzimidazolecarboxylate.

About 10 grams of 3A molecular sieve were added to 150 ml. of 2B ethanoland the mixture was stirred for about one-half hour before furtheradditions. Five grams of the thiourea mixture (A) were added followed bythe addition of 5 g. of yellow mercuric oxide. The reaction mixture wasrefluxed for 16 hours with brisk stirring. After cooling, the mixturewas filtered. The filtrate was evaporated to dryness in vacuo. Theresidue was taken up in ethyl acetate and filtered. The filtrate wasconcentrated by boiling to one-third the original volume. The productcrystallized upon cooling to yield 300 mg. of ethyl2-methylamino-5-benzimidazolcarboxylate, m.p. about 247°-249° C.

Analysis C₁₁ H₁₃ N₃ O₂ : MW 219. Calcd: C, 60.45; H, 5.54. Found: C,59.96; H, 6.14.

EXAMPLE 6 2-(2-Aminobenzimidazole-5-yl)propionic acid. (A)2-(3-Nitro-4-acetamidophenyl)propionitrile

One hundred grams of 2-(4-aminophenyl)propionitrile was acetylated withacetic anhydride in pyridine at 100° C. for one hour. After recovery ofthe product, crystallization from ethanol yielded 113 g. of2-(4-acetamidophenyl)propionitrile, m.p. about 82°-84 ° C.

One equivalent, 42 ml., of 70 percent nitric acid was added to 300 ml.of acetic anhydride cooled to 10° C. The acid solution was cooled bymeans of an ice-salt bath while 125 g. of the acetamido compound wasadded over a period of about 3-5 minutes with efficient stirring. Duringthe addition the reaction temperature rose to about 25° C. for about 10minutes. The mixture was stirred at 100° C. for two hours and thenallowed to come to room temperature for 3 hours. The mixture was pouredonto 500 g. of ice and the ice was allowed to melt. The insolubleproduct was filtered, dried, and recrystallized from ethanol-carbontetrachloride to yield 96 g. of2-(3-nitro-4-acetamidophenyl)propionitrile, m.p. about 98°-99° C.,yellow crystals.

(B) 2-(3-Nitro-4-aminophenyl)propionic acid

Forty grams of 2-(3-nitro-4-acetamidophenyl)propionitrile and 100 ml. ofconcentrated hydrochloric acid were refluxed under nitrogen for 4 hours.The cooled acid solution was filtered and the filtrate was brought to pH5 with 50 percent sodium hydroxide. The propionic acid product wasfiltered, washed with cold water and dried to yield 36 g. of2-(3-nitro-4-aminophenyl)propionic acid m.p. about 126°-127° C.

(C) 2-(3,4-Diaminophenyl)propionic acid

Four grams of the nitro acid obtained above was dissolved in 150 ml. ofethanol and 25 ml. of water. The mixture was hydrogenated at 60 psi atroom temperature over 250 mg. of 10 percent palladium-on-carbon. Thecatalyst was filtered and the filtrate was evaporated to dryness. Theresidue was crystallized from ethanol after carbon treatment to yield2-(3,4-diaminophenyl)propionic acid, m.p. 142°-145° C., dec.

(D) 2-(2-Aminobenzimidazol-5-yl)propionic acid

The diamino acid obtained above, 7.75 g., was dissolved in 300 ml. ofwater and the solution was cooled to 15° C. One equivalent of cyanogenbromide, 4.55 g., was added with stirring. Precipitation of solidoccurred during the addition, but the solid dissolved completely withinabout 3 hours. Later, a different solid precipitated. The second solid(I) was filtered, washed with water and was dried. The yield of solid Iwas 1.6 g. The filtrate was brought to pH 6 with 50 percent sodiumhydroxide. A yellow solid (II) precipitated. Solid II was filtered,washed with water, and dried to yield 5.8 g. Solids I and II wereidentical, yielding 7.4 g. of 2-(2-aminobenzimidazol-5-yl)propionicacid, m.p. about 300° C.

EXAMPLE 7 2-Amino-5-Trifluoromethylbenzimidazole (A)3,4-Diaminobenzotrifluoride

Eight grams of 5 percent palladium-on-carbon and 275 g. of3-nitro-4-aminobenzotrifluoride were added to 1.2 l. of 2B ethanol. Thenitro compound was reduced under 60 psi of hydrogen with Raney nickel atroom temperature for 1 hour. The reduction was exothermic. The catalystwas filtered and the filtrate was evaporated to dryness in vacuo. Theproduct was crystallized from ethanol-water to yield 135 g. of3,4-diaminobenzotrifluoride, m.p. 51°-53° C.

(B) 2-Amino-5-trifluoromethylbenzimidazole

One hundred seventy grams (0.96 m.) of 3,4-diaminobenzotrifluorideobtained above were suspended in 1.3 l. of water. Cyanogen bromide,101.7 g. (0.96 m.), was added portionwise to the stirred mixture whilethe reaction temperature was maintained below 45° C. by means of an icebath. The mixture was stirred overnight at room temperature. Thereaction mixture was filtered. Sodium hydroxide, 38.40 (0.96 m.) in 500ml. of water, was added to the filtrate. The basic filtrate wasextracted with ethyl acetate. The extract was washed with water anddried (MgSO₄). The ethyl acetate solution was evaporated in vacuo to asmall volume and n-hexane was added to induce crystallization of theproduct. The yield of 2-amino-5-trifluoromethylbenzimidazole was 173.7g., m.p. 143°-149° C.

EXAMPLE 8 2-Amino-5-Methylsulfonylbenzimidazole (A)4-Methylsulfonyl-o-phenylenediamine

Eighty grams of (p-chlorophenyl) methyl sulfone was nitrated with 64 g.of nitric acid in 400 ml. of concentrated sulfuric acid. After recoveryof the crude product, the nitro sulfone, had m.p. 110°-120° C.

Ninety-five grams of the crude (3-nitro-4-chlorophenyl) methyl sulfonewas ammoniated with 200 ml. of liquid ammonia in 200 ml. of 2B ethanolin a sealed autoclave at 150° C. for 6 hours. After cooling and ventingthe autoclave, the reaction mixture was poured into water. Theprecipitated product was filtered and recrystallized fromethanol-acetone to yield 53.4 g. of (3-nitro-4-aminophenyl) methylsulfone, m.p. 197°-199° C.

Forty-nine grams of the (3-nitro-4-aminophenyl) methyl sulfone weredissolved in 1 l. of ethanol and 1.5 g. of 5 percent Ruthenium-on-carbonwere added with stirring. Twenty-three grams of hydrazine hydrate areadded and the mixture was refluxed for 1 hour. The catalyst was filteredand the filtrate was evaporated to dryness in vacuo. Water was added tothe residue, and the product was recovered by filtration to yield 33.6g. of 4-methylsulfonyl-o-phenylenediamine, m.p. 156°-157° C.

(B) 2-Amino-5-methylsulfonylbenzimidazole

One mole, 186.1 g., of 4-methylsulfonyl-o-phenylenediamine was suspendedin 1.2 l. of water with stirring. One mole, 106 g., of cyanogenbromidewas added portionwise to the reaction mixture. The reaction mixture wasstirred for 4 hours and then filtered. Sodium hydroxide, 39 g. (1 m.) in500 ml. of water, was added to the filtrate. The aqueous mixture wascooled in an ice bath and the product crystallized. The product wascollected and dried before crystallization from ethanol-ether; yield 200g., m.p. 233°-238° C.

EXAMPLE 9 2-Amino-5-Cyanobenzimidazole (A) 4-Acetamidobenzonitrile

One mole (118 g.) of p-aminobenzonitrile was dissolved in 200 ml. ofpyridine. One mole (103 g.) of acetic anhydride was added to thepyridine solution and the reaction mixture was warmed on the steam bath(80° C.) for about 90 minutes. The mixture solidified completely. Coldwater was added to the solid and the product was broken up and pouredinto 2 l. of water. The product was filtered and the filter cake wasbroken up and washed with 1 N hydrochloric acid to extract startingmaterial. The acid washed product was collected and washed again withcold water until the washings tested neutral. The neutral product wascollected and dried to yield 149 g. of 4-acetamidobenzonitrile, m.p.205°-207° C.

(B) 3-Nitro-4-acetamidobenzonitrile

Sixty-seven grams of potassium nitrate were gradually stirred into 300ml. of concentrated sulfuric acid at 9° C. to form a paste. Fifty gramsof 4-acetamidobenzonitrile were added portionwise to the cold acidmixture. The reaction mixture was maintained at -5° C. for about onehour. The thick mixture was poured onto cracked ice. The product wascollected and washed with cold water. The wet solid was addedportionwise to about 400 ml. of warm acetic anhydride very carefully.Water was added to destroy the excess anhydride. The nitro product wascollected and recrystallized from ethanol to yield 25.5 g. of3-nitro-4-acetamidobenzonitrile m.p. 127°-129° C. A second crop, 23 g.,was obtained.

(C) 3-Nitro-4-aminobenzonitrile

One-tenth mole (20.5 g.) of 3-nitro-4-acetamidobenzonitrile wasdissolved in 0.5 l. of methylene chloride and 10 g. of dry pyridine.Phosphorus pentachloride (22.5 g.) was added and the reaction mixturewas stirred at room temperature for 3 hours. The mixture was cooled to0° C. and 51 ml. of isobutanol were added dropwise to the cold mixture.The mixture was allowed to come to room temperature and the solventswere evaporated to dryness in vacuo. The residue was crystallized fromwater to yield 12.5 g. of 3-nitro-4-aminobenzonitrile, m.p. 154.5°-156°C.

(D) 2-Amino-5-cyanobenzimidazole

3-Nitro-4-aminobenzonitrile (12.5 g.) was hydrogenated at 60 psi withRaney nickel in ethyl acetate at room temperature. The catalyst wasfiltered and the filtrate was evaporated to dryness in vacuo to providethe crude diamine.

The crude 3,4-diaminobenzonitrile (13.3 g.) was stirred in 450 ml. ofwater. Cyanogen bromide (10.6 g.) was added and the mixture was stirredat room temperature for 3 hours. The reaction mixture rose to 27° C.After reaction, the mixture was filtered to remove some tarry material.The filtrate was basified with sodium carbonate. The basic solution wasfiltered to remove any dark material, and the filtrate was extractedwith ethyl acetate. The ethyl acetate extract was evaporated in vacuo.The residue was crystallized from ethyl acetate-n-hexane to yield 6.4 g.of 2-amino-5-cyanobenzimidazole, m.p. 223°-226° C.

Analysis C₈ H₆ N₄ : MW 158. Calcd: C, 60.75; H, 3.82. Found: C, 60.26;H, 4.04.

EXAMPLE 10 Ethyl1-Dimethylaminosulfonyl-2-Amino-6-benzimidazolecarboxylate

Fifty grams (0.24 mole) of ethyl 2-amino-5(6)-benzimidazolecarboxylate,200 ml. of acetone and 50 ml. of triethylamine were stirred together.Dimethylsulfamoyl chloride, 35.8 g. (0.25 mole), was added dropwise tothe reaction mixture. The reaction mixture was refluxed for 100 hours.The precipitated product was filtered, washed with water, andrecrystallized from methanol to give 15 g. (20 percent yield) of ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate.

Analysis C₁₂ H₁₅ N₄ SO₄ : MW 312. Calcd: C, 46.29; H, 4.86; N, 18.00.Found: C, 46.06; H, 5.10; N, 17.78.

EXAMPLE 11 Ethyl1-Dimethylaminosulfonyl-2-Acetamido-6-benzimidazolecarboxylate

Three grams (9.6 mmole) of ethyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate were stirredovernight with 30 ml. of acetic anhydride. The thick product slurry waspoured into water. The product was filtered, washed with water and driedto yield 3 g. (88 percent) of ethyl1-dimethylaminosulfonyl-2-acetamido-6-benzimidazolecarboxylate, m.p.155°-157° C.

Analysis C₁₄ H₁₈ N₄ O₅ S: MW 354. Calcd: C, 47.45; H, 5.12; N, 15.81.Found: C, 47.28; H, 5.16; N, 15.60.

EXAMPLE 12 Ethyl1-Isopropylsulfonyl-2-Amino-5(6)-Benzimidazolecarboxylate

Five grams (25.0 mmole) of ethyl 2-amino-5-benzimidazolecarboxylate and3 ml. of triethylamine were stirred with 150 ml. of acetone.Isopropylsulfonyl chloride, 3.6 g. (25.0 mmole) dissolved in 10 ml. ofacetone, was added dropwise to the stirred reaction mixture. The mixturewas refluxed for 20 hours. After cooling, the mixture was filtered andthe filtrate was evaporated to dryness in vacuo. The residue was takenup in a minimum amount of methanol and allowed to stand overnight atroom temperature. The crystalline product was filtered and the materialwas washed with a small amount of cold methanol and ether. A second cropwas obtained from the combined washings to yield 280 mg. of ethyl1-(isopropylsulfonyl)-2-amino-6-benzimidazolecarboxylate, m.p. about165°-167° C., colorless crystals. The material was established as the6-isomer by nuclear magnetic resonance (NMR) in dimethylsulfoxide.

The 5-isomer was recovered from the original methanol filtrate to yield365 mg. of ethyl 1-isopropylsulfonyl-2-amino-5-benzimidazolecarboxylate,m.p. about 166°-168° C., orange crystals. The structure was confirmed byNMR in dimethylsulfoxide.

Analysis C₁₃ N₁₇ N₃ O₄ S: MW 311. Calcd: C, 50.15; H, 5.50; N, 13.50.Found: 5-isomer: C, 49.86; H, 5.48; N, 13.24. 6-isomer: C, 49.92; H,5.26; N, 13.44.

EXAMPLE 13 Ethyl1-(N-Methyl-N-Ethylaminosulfonyl)-2-Amino-5(6)-Benzimidazolecarboxylate

Ten grams (50.0 mmoles) of ethyl 2-amino-5-benzimidazolecarboxylate and10 ml. of triethylamine were stirred in 40 ml. of dry acetone. Eightgrams (50.0 mmoles) of N-methyl-N-ethylsulfamoyl chloride were added andthe mixture was refluxed for 48 hours. The reaction mixture was filteredafter cooling and the filtrate was concentrated to one-half the originalvolume in vacuo. The mixture of isomers crystallized from solution uponstanding overnight. The product mixture was collected and washed with asmall amount of cold methanol.

Analysis C₁₂ H₂₈ N₄ O₄ S: MW 326. Calcd: C, 47.84; H, 5.56; N, 17.17.Found: C, 48.09; H, 5.49; N, 16.97.

EXAMPLE 14 Separation of Ethyl1-(N-Methyl-N-Ethylaminosulfonyl)-2-Amino-6-Benzimidazolecarboxylate bybasic hydrolysis

Four and six-tenths grams (14 mmoles) of an isomeric mixture of ethyl1-(N-methyl-N-ethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate,1.7 g. (30 mmoles) of potassium hydroxide and 50 ml. of water and wererefluxed for 45 minutes with stirring. After cooling, the insoluble6-isomer ethyl ester was collected by filtration. The yield was 450 mg.of ethyl1-(N-methyl-N-ethylaminosulfonyl)-2-amino-6-benzimidazolecarboxylate,m.p. about 170°-171° C.

Analysis C₁₂ N₁₈ N₄ O₄ S: MW 326. Calcd: C, 47.84; H, 5.56; N, 17.17.Found: C, 47.76; H, 5.66; N, 16.95.

The basic filtrate was neutralized with 1 N hydrochloric acid. The solidwhich precipitated was collected to yield 2 g. of1-(N-methyl-N-ethylaminosulfonyl)-2-amino-5-benzimidazolecarboxylate asa monohydrate, m.p. about 197°-199° C.

Analysis C₁₁ H₁₄ N₄ O₄ S.H₂ O: MW 316. Calcd: C, 41.77; H, 5.07; N,17.72. Found: C, 42.62; H, 4.49; N, 17.89.

Further acidification of the neutral filtrate provided a mixture of 5and 6 carboxylic acids in small amount.

EXAMPLES 15 and 161-Dimethylaminosulfonyl-2-Amino-5(6)-Benzimidazolecarboxamide (A)1-Dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylic acidhydrazide

Three grams of ethyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate (Ex. 10),50 ml. of methanol and 6 ml. of hydrazine hydrate were refluxed forabout 100 hours. The hydrazide product crystallized out of solutionduring the reaction. The hot reaction mixture was filtered to yield 200mg. of 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylic acidhydrazide, m.p. about 229°-230° C. dec, confirmed by nuclear magneticresonance spectrum.

Analysis C₁₀ H₁₄ N₆ O₃ S: MW 298. Calcd: C, 40.30; H, 4.70; N, 28.20.Found: C, 40.21; H, 4.54; N, 28.33.

Upon cooling, the filtrate yielded a solid which was collected. Thesolid was a mixture of isomeric acid hydrazides. The subsequentfiltrates yielded two crops of crystals upon concentrating the coolingto give a combined yield of 350 mg. of1-dimethylaminosulfonyl-2-amino-6-benzimidazole carboxylic acidhydrazide hydrate, m.p. about 205°-206° C., confirmed by NMR.

Analysis C₁₀ H₁₄ N₆ O₃ S.H₂ O: MW 316. Calcd: C, 37.97; H, 5.06; N,26.58. Found: C, 38.40; H, 4.41; N, 26.15.

(B) 1-Dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxamide hydrate

Two grams of 1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxylicacid hydrazide, 8 g. of Raney nickel and 100 ml. of 2B ethanol wererefluxed for 4 hours. The cooled mixture was filtered and the catalystwas washed with ethanol. The ethanol washings were combined with thefiltrate. The ethanol solution was evaporated to dryness in vacuo. Theresidue was dissolved in methanol and the solution was filtered througha fritted glass funnel having 4 mm. layer of alumina. The methanolfiltrate was concentrated in vacuo to provide1-dimethylaminosulfonyl-2-amino-5-benzimidazolecarboxamide hydrate, m.p.about 208°-209° C.

Analysis C₁₀ H₁₃ N₅ O₃ S.H₂ O: MW 301. Calcd: C, 39.87; H, 4.98; N,23.25. Found: C, 40.05; H, 4.78; N, 22.81.

(C) 1-Dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxamide

The procedure of method B above was repeated with 2.5 g. of1-dimethylaminosulfamoyl-2-amino-6-benzimidazolecarboxylic acidhydrazide and 10 g. of Raney nickel to yield1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxamide, m.p. about206°-208° C. A second crop was obtained from the mother liquors.

Analysis C₁₀ H₁₃ N₅ O₃ S: MW 283. Calcd: C, 42.40; H, 4.63; N, 24.72.Found: C, 43.56; H, 4.53; N, 24.60.

EXAMPLE 17 Isobutyl1-Dimethylaminosulfonyl-2-Acetamido-5(6)-Benzimidazolecarboxylate

(A) Six grams (0.018 mole) of1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidobtained from the basic hydrolysis (Ex. 14) of the ethyl ester (Ex. 11),was dissolved in 15 ml. of dimethylformamide (DMF).1,1'-Carbonyldiimidazole, 3.6 g., was added to the mixture withstirring. Forty five milliliters of isobutanol that had been treatedwith about 200 mg. of sodium hydride was added to the reaction mixture.The reaction was continued at room temperature for about 12 hours. Themixture was poured into 1.2 l. of water. After an initial extractionwith n-hexane, the aqueous phase was extracted with ethyl acetate. Theethyl acetate extract was washed with water and dried over molecularsieve. The ethyl acetate solution was evaporated in vacuo to give anisobutanol residue. Ester product crystallized from the isobutanolresidue upon standing. The product was crystallized from isobutanol togive 27 g. of the 6-isomer, isobutyl1-dimethylaminosulfonyl-2-acetamido-6-benzimidazolecarboxylate, m.p.151°-152° C., confirmed by NMR.

Analysis C₁₆ H₂₂ N₄ O₅ S: MW 382. Calcd: C, 50.25; H, 5.80; N, 14.43.Found: C, 50.46; H, 5.68; N, 14.43.

(B) The isobutanol filtrates and mother liquors from the crystallizationof the 6-isomer were concentrated to about one-half the original volumein vacuo to yield about 2 g. of the 5-isomer, isobutyl1-dimethylaminosulfonyl-2-acetamido-5-benzimidazolecarboxylate, m.p.105°-108° C., confirmed by NMR.

Analysis C₁₆ H₂₂ N₄ O₅ S: MW 382. Calcd: C, 50.25; H, 5.80; N, 14.43.Found: C, 50.24; H, 5.69; N, 14.89.

EXAMPLE 18 Isobutyl1-Dimethylaminosulfonyl-2-Amino-6-Benzimidazolecarboxylate

One gram (2.6 mmole) of isobutyl1-dimethylaminosulfonyl-2-acetamido-6-benzimidazolecarboxylate (Ex. 17)was suspended in 30 ml. of water with 2 pellets (200 mg.) of potassiumhydroxide. The mixture was refluxed for 2.5 hours with stirring. Thehydrolyzed product was collected to yield 100 mg. of isobutyl1-dimethylaminosulfonyl-2-amino-6-benzimidazolecarboxylate, m.p.197°-198° C.

Analysis C₁₄ H₂₀ N₄ O₄ S: MW 340. Calcd: C, 49.40; H, 5.92; N, 16.46.Found: C, 49.67; H, 5.97; N, 16.56.

EXAMPLE 19 Cyclohexylmethyl1-Dimethylaminosulfonyl-2-Acetamido-5(6)-Benzimidazolecarboxylate

Six grams (0.018 mole) of1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidobtained from the basic hydrolysis of the ethyl ester (Ex. 11), 10 g. ofcyclohexylmethanol treated with 200 mg. of 50 percent sodium hydride,and 1,1'-carbonyldiimidazole were reacted in DMF by the method ofExample 17 to yield 1 g. of cyclohexylmethyl1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylate as anisomeric mixture.

Analysis C₁₉ H₂₆ N₄ O₅ S: MW 422. Calcd: C, 54.01; H, 6.20; N, 13.26.Found: C, 53.94; H, 6.01; N, 13.16.

EXAMPLE 20 Benzyl1-Dimethylaminosulfonyl-2-Amino-5(6)-benzimidazolecarboxylate

One gram (3.1 mmole) of potassium1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate wassuspended in 10 ml. of dimethylformamide (DMF). Four tenths of amilliliter (3.1 mmole) of benzylchloride in 5 ml. of DMF were addeddropwise with stirring. The reaction was stirred at room temperature forabout 12 hours. The reaction mixture was decanted from a heavyprecipitate and poured into water. Product precipitated from the aqueoussolution. An NMR spectrum indicated that both the original precipitateand the aqueous precipitate were the expected benzyl ester. The yieldwas about 600 mg. (50 percent) of benzyl1-dimethylaminosulfonyl-2-amino-5(6)-benzimidazolecarboxylate.

Analysis (1/3 DMF adduct): MW 398. Calcd: C, 54.27; H, 5.02; N, 15.33.Found: C, 54.64; H, 4.95; N, 15.95.

EXAMPLES 21-33

The following esters were prepared by the methods of Examples 17-20.

                                      TABLE IV                                    __________________________________________________________________________    Esters of 1-Dimethylaminosulfonyl-                                            2-amino-5(6)-benzimidazolecarboxylic acid                                                         Analysis (Percent)                                                      MP    Theory   Found                                            No. Ester*    °C.                                                                          C  H  N  C  H  N                                          __________________________________________________________________________    21  (6)-methyl                                                                              211-213                                                                             44.29                                                                            4.73                                                                             18.78                                                                            45.28                                                                            4.72                                                                             18.21                                      22  propyl          47.84                                                                            5.57                                                                             17.17                                                                            47.62                                                                            5.31                                                                             16.92                                      23  (6)-isopropyl                                                                           173-175                                                                             47.84                                                                            5.56                                                                             17.17                                                                            48.08                                                                            5.42                                                                             16.96                                      24  (6)-butyl 150-153                                                                             49.40                                                                            5.92                                                                             16.40                                                                            49.64                                                                            5.98                                                                             16.20                                      25  (6)-isobutyl                                                                            197-198                                                                             49.40                                                                            5.92                                                                             16.46                                                                            49.67                                                                            5.97                                                                             16.56                                      26  (5)-neopentyl                                                                           157-160                                                                             50.83                                                                            6.26                                                                             15.81                                                                            51.06                                                                            6.03                                                                             15.75                                      27  (6)-neopentyl                                                                           196-198                                                                             50.83                                                                            6.26                                                                             15.81                                                                            50.99                                                                            6.05                                                                             15.99                                      28  (6)-cyclohexyl                                                                          180-184                                                                             52.44                                                                            6.05                                                                             15.29                                                                            52.67                                                                            6.29                                                                             15.48                                      29  octyl           54.53                                                                            7.12                                                                             14.13                                                                            54.26                                                                            6.87                                                                             13.85                                      30  cyclohexylmethyl                                                                              53.68                                                                            6.32                                                                             14.74                                                                            53.85                                                                            6.38                                                                             13.71                                      31  α-methylbenzyl                                                                          55.66                                                                            5.19                                                                             14.42                                                                            56.83                                                                            5.41                                                                             13.87                                      32  allyl           48.29                                                                            4.68                                                                             17.33                                                                            48.50                                                                            4.47                                                                             17.30                                      33  propargyl       48.59                                                                            4.08                                                                             17.44                                                                            48.32                                                                            4.06                                                                             17.31                                      __________________________________________________________________________     *Number indicates ester isomer otherwise the ester is an isomer mixture. 

EXAMPLES 34-49

The following esters were prepared by the methods of Examples 17-20.

                                      Table V.                                    __________________________________________________________________________    Esters of 1-Dimethylaminosulfonyl-                                            2-acetamido-5(6)-benzimidazolecarboxylic acid                                                    Analysis (Percent)                                                       MP   Theory   Found                                             NO.                                                                              Ester*     ° C.                                                                        C  H  N  C  H  N                                           __________________________________________________________________________    34 (5)-ethyl  167-168                                                                            47.45                                                                            5.12                                                                             15.81                                                                            47.60                                                                            5.19                                                                             16.03                                       35 (6)-ethyl  201-202                                                                            47.45                                                                            5.12                                                                             15.81                                                                            47.28                                                                            5.16                                                                             15.60                                       36 isopropyl       48.90                                                                            5.47                                                                             15.21                                                                            48.92                                                                            5.76                                                                             15.46                                       37 (5)-isobutyl                                                                             105-108                                                                            50.25                                                                            5.80                                                                             14.65                                                                            50.24                                                                            5.69                                                                             14.89                                       38 (6)-isobutyl                                                                             151-152                                                                            50.25                                                                            5.80                                                                             14.65                                                                            50.46                                                                            5.68                                                                             14.43                                       39 sec-butyl       50.26                                                                            5.76                                                                             14.66                                                                            49.94                                                                            5.60                                                                             14.35                                       40 cyclobutyl      50.52                                                                            5.30                                                                             14.73                                                                            50.39                                                                            5.08                                                                             14.56                                       41 neopentyl       51.52                                                                            6.06                                                                             14.14                                                                            51.73                                                                            5.98                                                                             14.29                                       42 cyclohexyl      52.93                                                                            5.92                                                                             13.72                                                                            53.04                                                                            5.68                                                                             13.90                                       43 (5)-cyclopropylmethyl                                                                    109-112                                                                            50.79                                                                            4.79                                                                             14.81                                                                            50.58                                                                            5.00                                                                             14.73                                       44 (6)-cyclopropylmethyl                                                                    146.149                                                                            50.79                                                                            4.79                                                                             14.81                                                                            50.55                                                                            5.02                                                                             14.97                                       45 1-cyclopropylethyl                                                                            51.76                                                                            5.62                                                                             14.20                                                                            51.47                                                                            5.40                                                                             14.29                                       46 cyclohexylmethyl                                                                              54.01                                                                            6.20                                                                             13.26                                                                            53.94                                                                            6.01                                                                             13.16                                       47 (3-methylcyclohexyl)-                                                                    53.03                                                                              6.47                                                                             12.83                                                                            54.87                                                                            6.66                                                                             12.68                                             methyl                                                                     48 (5)-phenyl 167-170                                                                            53.59                                                                            4.75                                                                             13.89                                                                            53.88                                                                            4.59                                                                             13.61                                       49 (6)-phenyl 215-220                                                                            53.59                                                                            4.75                                                                             13.89                                                                            53.73                                                                            5.03                                                                             13.79                                       __________________________________________________________________________     *Number indicates ester isomer otherwise the ester is an isomer mixture. 

EXAMPLE 501-Dimethylaminosulfonyl-2-Amino-5(6)-N-Ethylbenzimidazolecarboxamide

(A) Six grams of1-dimethylaminosulfonyl-2-acetamido-5(6)-benzimidazolecarboxylic acidwere dissolved in 15 ml. of DMF. Three and six-tenths grams of1,1'-carbonyldiimidazole were added to the stirred mixture. Ethylamine,20 ml. (excess), was added and the reaction was stirred for about 12hours. The mixture was poured into a liter of water. The aqueoussolution was extracted with ethyl acetate. The ethyl acetate extract wasdried over molecular sieve. The ethyl acetate solution was concentratedto a small volume in vacuo. The 6-isomer crystallized to yield 2.5 g. of1-dimethylaminosulfonyl-2-amino-6-N-ethylbenzimidazolecarboxamide, m.p.215°-216° C., the 2-acetyl group being lost by aminolysis.

Analysis C₁₄ H₁₈ N₅ O₄ S: MW 356. Calcd. C, 46.29; H, 5.50; N, 22.49.Found: C, 46.11; H, 5.35; N, 22.25.

(B) The 5-isomer was recovered from the ethyl acetate filtrates to yield2.1 g. of1-dimethylaminosulfonyl-2-amino-5-N-ethylbenzimidazolecarboxamide, m.p.155°-160° C.

Analysis C₁₄ H₁₈ N₅ O₄ S: MW 352. Calcd: C, 46.29; H, 5.50; N, 22.49.Found: C, 46.54; H, 5.24; N, 21.93.

EXAMPLE 51 Ethyl1-(2-Thiophene)sulfonyl-2-Amino-5(6)-benzimidazolecarboxylate

Five and five-tenths grams (0.027 m) of ethyl2-amino-5(6)-benzimidazolecarboxylate were dissolved in 100 ml. ofacetone and 3 ml. of triethylamine. Five grams of 2-thiophenesulfonylchloride dissolved in 10 ml. of acetone were added dropwise to thereaction mixture with stirring. The mixture was refluxed for 24 hours.The amine salt was filtered and the filtrate was evaporated to drynessin vacuo. The residue was recrystallized from methanol to yield 3.6 g.(38 percent) of ethyl1-(2-thiophene)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate as anisomeric mixture via NMR.

Analysis: MW 351. Calcd: C, 47.85; H, 3.73; N, 11.96. Found: C, 47.67;H, 3.84; N, 11.76.

EXAMPLE 52 2-Acetamido-4-methylthiazol-5-yl

Eight and one-tenth grams (0.04 m.) of ethyl2-amino-5(6)-benzimidazolecarboxylate were dissolved in 200 ml. ofacetone and 8 ml. of triethylamine. Ten grams (0.04 m.) of2-acetamido-4-methyl-5-thiazolesulfonyl chloride were added dropwise tothe reaction mixture with stirring. The mixture was refluxed for 24hours. Precipitate (A) was collected by filtration. The precipitate (A)was washed with water and dried to yield 2 g. of the 5-isomer of theproduct, m.p. 209°-210° C. dec. The filtrate was evaporated to drynessin vacuo. The residue was taken up in a small volume of methanol fromwhich 8.5 g. (50 percent yield) of ethyl1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylatewas obtained as an isomeric mixture, m.p. 190°-202° C. dec.

Analysis C₁₆ H₁₇ N₅ O₅ S₂ : MW 423. Calcd: C, 45.39; H, 4.02; N, 16.54.Found: C, 45.52; H, 4.43; N, 15.94.

EXAMPLE 53 Ethyl1-(2-Methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate

One and nin-tenths grams (9.3 mmole) of ethyl2-amino-5(6)-benzimidazolecarboxylate were dissolved in 20 ml. ofacetone and 1 ml. of triethylamine. Two grams of2-methylamino-5-thiadiazolesulfonyl chloride were added dropwise to thereaction mixture with stirring. The mixture was refluxed for 16 hours.The mixture was filtered and the filtrate was evaporated to dryness invacuo. The oily residue was taken up in methanol from which ethyl1-(2-methylamino-1,3,4-thiadiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylatecrystallized as an isomeric mixture.

Analysis C₁₃ H₁₄ N₆ O₄ S₂ : MW 382. Calcd: C, 40.83; H, 3.69; N, 21.98.Found: C, 40.59; H, 3.94; N, 21.78.

EXAMPLE 541-Dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole (A)2-Amino-5(6)-hydroxymethylbenzimidazole

Twenty-four and six-tenths grams of ethyl2-amino-5(6)-benzimidazolecarboxylate were suspended in 600 ml. oftetrahydrofuran (THF) under nitrogen. Ninety-six ml. (0.36 mole) ofsodium bis(2-methoxyethoxy)-aluminum hydride (RED-AL) in 400 ml. of THFwere added dropwise to the stirred reaction mixture at a rate such thatthe temperature did not exceed 35° C. The mixture was heated at refluxfor about 20 hours. The excess RED-AL was decomposed by the addition of30 ml. of water. The mixture was filtered and the filtrate wasevaporated in dryness in vacuo. The foamy residue was treated with 150ml. of ethyl acetate and 200 ml. of water. The aqueous emulsified phasewas separated. The aqueous phase was filtered to yield a yellow solid.The aqueous filtrate was evaporated in vacuo to yield a second crop. Thecombined yield was 12.3 g. (65 percent) of crude2-amino-5(6)-hydroxymethylbenzimidazole. An analytical sample of theisomeric mixture was prepared.

Analysis C₈ H₉ H₃ O: MW 163. Calcd: C, 58.88; H, 5.56; N, 25.75. Found:C, 58.65; H, 5.48; N, 25.54.

(B) 1-Dimethylaminosulfonyl-2-amino-5(6)-hydroxymethylbenzimidazole

Thirty millimoles, 4.9 g., of 2-amino-5(6)-hydroxymethylbenzimidazolewas dissolved in 40 ml. of acetone. Thirty millimoles, 3.03 g., oftriethylamine were added to the acetone solution followed by 4.32 g. (30mmoles) of dimethylsulfamoyl chloride. The mixture was heated at refluxfor about 17 hours. The mixture was poured into 25 ml. of water. Theaqueous mixture was extracted with chloroform. The chloroform extractwas washed successively with water and saturated sodium chloridesolution. The chloroform solution was filtered and dried. The chloroformwas evaporated to dryness in vacuo, to yield 5.5 g. (66 percent) ofcrude product as an isomeric mixture.

Seven grams of crude isomeric mixture were chromatographed over Woelmsilica gel using ethyl acetate as the eluant. The 6-isomer was collectedafter 6 l. of eluant had passed over the column. The yield was 1.02 g.of 1-dimethylaminosulfonyl-2-amino-6-hydroxymethylbenzimidazole, m.p.182°-183° C. (ethylacetate-methanol).

Analysis C₁₀ H₁₄ N₄ O₃ S: MW 270. Calcd: C, 44.43; H, 5.22; N, 20.73.Found: C, 44.37; H, 5.18; N, 20.44.

We claim:
 1. A compound of the formula ##STR3## wherein R₁ isthiazol-2-yl, 2-acetamido-4-methylthiazol-5-yl, 1,3,4-thiadiazol-2-yl,2-methyl-1,3,4-thiadiazol-5-yl, or 2-methylamino-1,3,4-thiadiazol-R₂ ishydrogen, formyl, acetyl or propionyl; R₃ is C₁ -C₈ alkoxycarbonyl,allyloxycarbonyl, proparglyloxycarbonyl, (C₃ -C₇ cycloalkyl)oxycarbonyl,(C₃ -C₇ cycloalkyl)methyloxycarbonyl, 1-(C₃ -C₇cycloalkyl)ethyloxycarbonyl, benzyloxycarbonyl,α-methylbenzyloxycarbonyl, phenoxycarbonyl, hydrazinocarbonyl, carboxy,carboxamido, N-(C₁ -C₄ alkyl)carboxamido, N-(C₁ -C₄ alkoxy)carboxamido,or cyano; and R₃ is at the 5 or 6 position.
 2. The compound of claim 1wherein R₁ is 2-acetamido-4-methylthiazol-5-yl.
 3. The compound of claim2 which is ethyl 1-(2-acetamido-4-methylthiazol-5-yl)sulfonyl-2-amino-5(6)-benzimidazolecarboxylate.
 4. The compound of claim1 which is ethyl1-(2-methylamino-1,3,4-thiadiazol-5-ylsulfonyl)-2-amino-5(6)-benzimidazolecarboxylate.